First Direct Evidence of Neuroinflammation - 'Encephalitis' - in ME/CFS

Thank you for your reply, I'm asking because inflammation would mean celldeath (right?) and I know it sounds (and looks, I sent you the link to a video) ridiculous but I think mine are recuperating which wouldn't be possible if...well.....dead. The same thing is happening throughout my body but it manifests differently (brain; májor pressure, eyes; trembling, and so on).

I'm cautious about what the Osaka study actually found - as I wrote on another thead:

"The Osaka City University study is promising but even that need not require actual inflamation of the brain, merely that the usual products of inflammation be present and caused by some as yet unexplained disease process. There's also the possibility that this small Japanese study has revealed something specific to a localised gene variant and replication needs to be done in diverse populations to address that, along with the usual prcesses of replication."

Of course one would hope that nature is abiding by Occam's Razor and the simplest explanation of 'evidence of inflamation = inflamation' is the right one, but in the case of ME I don't think that we can be certain without some very weighty numbers. It's become a sort of accepted coda amongst patients that - "the answer is out there" - and if only researchers had been looking in the right place then 'the answer' to ME would have been found years ago. And again of course that would be ideal because good, focussed and sustained research should be certain of getting the answer. But it may not be like that - ME may just be something that is very difficult to get at, something where there is an awful lot of evidence to be found, but where little or none of the evidence quite means what it is expected to mean.

Great write up Simon. We seem to have taken as slightly different although complementary slant in reporting this.
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My own feeling is that future research should be aimed at replicating and expanding our understanding of this as the central mechanism and common end point resulting from a range of potential triggers. I am slightly biased though !

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Thanks . And if you are talking about mecfs research on neuroinflammation, I totally agree it should be a priority.

I think for all of this, the first step needed is replication by the original authors using their improved design, which I understand has already started or will soon do so. Then other Qs come into play, including how it compares with other chronic illnesses and with acute infection. As Tony Komaroff said, what's needed is independent confirmation by multiple different labs. I wouldn't normally blog on such a small study, but as the findings tie in with so many other theories, and as an improved version of the study is already planned, I think this study deserves more attention.

Marco said:

I'm not sure I'd agree with the conclusion that this represent 'encephalitis' though - certainly not the encephalomyelitis as envisaged by Ramsey as discussed here :

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Re encephalitis, I took my cue from Tony Komaroff:

Prof Komaroff said:

"[If replicated] it would, for me, say that there is a low-grade, chronic encephalitis in these patients, that the image we clinicians have of encephalitis as an acute and often dramatic clinical presentation that can even be fatal has -- may have -- blinded us to the possibility that there may be that long-lasting -- many years long -- cyclic chronic neuroinflammation is underlying the symptoms of this illness."

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As for encephalomyelitis, the microglial and astrocytes that showed up as activated in the brain PET scan are also present in the spinal column, so it's plausible they too are activated - that would need a different PET scan to investigate. Again, this would be low-grade which as I understand it is not what is normally meant by encephalomyelitis. There again, my understanding was that Ramsay used encephalomyelitis because he thought that would explain the clinical symptoms he found (he didn't have direct evidence).

If the neuroinflammation evidence checks out Ramsay may have been on exactly the right lines - that's the only point I'm trying to make. I wouldn't want to push it too far, esp as this is a study on only 9 patients and didn't even look at the spinal column.

I wasn't aware that the Dubbo work was continuing which is great news as a predisposition to an enhanced immune response to common infections could be a key component in a 'multi-hit' scenario (conversely this enhanced response could be a symptom of already primed/activated glia - normal aging involves glial priming and the elderly have an often catastrophic enhanced immune reaction to minor stressors). Another possible contributor is SNPs that result in exaggerated microglial activation.

As @Legendrew says, there is a vast range of possible triggers that could lead to glial priming and activation....

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We must talk before I write my next blog! Hugh Perry's hypothesis is about microglial priming, so that people have an exaggerated immune response.

Thanks . And if you are talking about mecfs research on neuroinflammation, I totally agree it should be a priority.

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Yes indeed.

Re encephalitis, I took my cue from Tony Komaroff:

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I appreciate that and I agree that its an 'itis' but this type of neuroinflammation is also found in conditions such as post concussion syndrome, complex regional pain syndrome, in normal aging (as previously mentioned) neurodegenerative diseases and in what were considered 'classic' psychiatric disorders such as major depression, bipolar and OCD. It may just be semantics but I doubt few would refer to these conditions as reflecting 'encephalitis' even if neuroinflammation is now recognised as playing a central role.

I appreciate that and I agree that its an 'itis' but this type of neuroinflammation is also found in conditions such as post concussion syndrome, complex regional pain syndrome, in normal aging (as previously mentioned) neurodegenerative diseases and in what were considered 'classic' psychiatric disorders such as major depression, bipolar and OCD. It may just be semantics but I doubt few would refer to these conditions as reflecting 'encephalitis' even if neuroinflammation is now recognised as playing a central role.

the presence of neuroinflammation (which our post-mortem group has already reported in relation to dorsal root ganglionitis – part of the peripheral nervous system) does not necessarily mean that encephalomyelitis is present.
A lot of autoimmune and inflammatory diseases, as well as neurological diseases, have a neuroinflammatory component – but the clinical presentation and pathology is not an encephalomyelitis

I continue to take the view that ME/CFS has a neuroinflammatory component

But I still don’t think that ME/CFS is going to turn out to be what neurologists and pathologists would regard as an encephalomyelitis. – i.e. extensive inflammation involving the brain and spinal cord

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So to avoid confusion I will stick with neuroinflammation. However, I do think that Ramsay's implicit point, that the symptoms indicated a problem in the brain, may eventually prove right.

Well I think it's fairly well known I'm a fan of the autoimmune hypothesis but the interesting thing with this form of neuroinflammation is that there are a plethora of ways to arrive at the same state, as you mention. If this research holds true during replication (and I know that's a very big if!) then we could perhaps be looking at differing sub-groups. It's only logical that if autoimmunity is perpetuating your neuroinflmmation that the treatment would be different than if it was a virus causing it and the same goes for nearly ever different event that could perpetuate it.

I'm not suggesting this is a treatment for ME/CFS or any other case of neuroinflammation, but it does suggest another route to treatment, even if it wasn't treating the cause.

Another possibility is that the chronic neuroinflammation is chronic because of a problem with the microglia, and not because of any stimulus outside the brain, and again in that case a microglial inhibitor might be appropriate. Though of course, you need your microglia to get active some of the time, that's what they are there for.

Probably the most important piece of work on the role of sickness behaviour -- and cytokines -- in ME/CFS came from the landmark "Dubbo" studies.

The researchers found that typically, 20% of those with glandular fever and two other infections developed CFS after six months. And crucially, what predicted the length of the illness (and chance of developing CFS) wasn't psychological factors, but the severity of the initial 'acute illness', or sickness behaviour.

I'm a little concerned about this bit, do you know if the scans were analyzed blind ?

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I'd imagine you would compare the scans of controls and patients alongside one another and it would allow you to clean up a lot of the 'noise', it's far from a perfect way to analyse this kind of data but it lets you see on a qualitative level whether there is any significant difference which is what I believe this study is reporting.

I'm a little concerned about this bit, do you know if the scans were analyzed blind ?

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Not sure, but they did prespecify which areas they considered:

Image Data Analysis
All 11C-(R)-PK11195 BPND images were normalized to the Montréal
Neurologic Institute space, smoothed with an isotropic 8-mm
gaussian kernel, and analyzed by Statistical Parametric Mapping 5
software (SPM5; Wellcome Department of Cognitive Neurology) using
a categoric design. The between-group comparison (CFS/ME
patients vs. healthy controls) of 11C-(R)-PK11195 BPND and correlation
analysis of 11C-(R)-PK11195 BPND values and clinical scores
were performed on a voxel-by-voxel basis using t statistics with the
statistical threshold set at a P value of less than 0.005 at the voxel level
and a P value of less than 0.05 with a correction for multiple comparisons
at the cluster level for the entire brain (familywise error). The
regions of interest for the cingulate cortex, hippocampus, amygdala,
thalamus, midbrain, and pons were defined from the Wake Forest
University PickAtlas (21) and applied to the smoothed images.

Thanks on both counts. I was finishing the blog off yesterday and was having a rough one - I was sure the figure was around 12% but could only find one suggesting 20% so lazily went with that. Blog now corrected.

Thank you for your reply, I'm asking because inflammation would mean celldeath (right?) and I know it sounds (and looks, I sent you the link to a video) ridiculous but I think mine are recuperating which wouldn't be possible if...well.....dead. The same thing is happening throughout my body but it manifests differently (brain; májor pressure, eyes; trembling, and so on).

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Activation of the microglia (or astrocytes) themselves does not cause their cell death. Their activation will lead to other changes which may or may not lead to cell death/apoptosis for other cells - I think it would depend on other things too, such as other signalling molecules in the micro environment.

its worth looking into memantine as a treatment for inflammation in ME as this drug has been around awhile and can be repurposed, so no having to wait for long trials and studies for its approval, possibly get a doctor now to prescribe it off label.

Memantine has effects on lowering tnf as well as nmda/glutamate, another cause of inflammation. It also helps increase dopamine which is useful for increasing mood and energy, decreasing pain and many other functions. Its also known to increase cortisol in certain parts of the brain which would also enhance energy. The nmda antagonist effects can also improve gaba sensitivity, so maybe help those with that tired wired feeling??

I think its an interesting drug that could be very useful in this reguard??

I think the evidence of neuro-inflammation, whether or not you consider that to be encephalitis, goes back to 1955. After the outbreaks in Adelaide, Australia, in the late 1940s they did some research. One line of research injected patient blood into animals. In 1955 it was published that the blood in monkeys resulted in particular kinds of spinal lesions, with immune infiltration. That is, I think not coincidentally, the kind of thing they have found in ME autopsy results.

In inflammation there is growing evidence that brain cells do not so much die as become dormant. So long as inflammation persists they do not function. Remove the inflammation and they have restored function. This is still a new and controversial area though.